Project Summary Salmonella is a common and important pathogen that kills millions of people each year, primarily children in developing countries. It was the first organism to be used as a bioterrorist weapon in the US and is listed as category B in the NIH list of BT agents (S. enterica as we describe here). The primary goal of my research is to use Salmonella as a model to understand how intracellular pathogens manipulate host cells to cause disease. Using our expertise with the Salmonella/macrophage model, coupled with genetics, molecular biology and transcriptional profiling, we will further our understanding of how intracellular pathogens regulate virulence gene expression. Our hypothesis is that multiple regulators respond to different cues within cells and that the signal becomes integrated, perhaps by one or a few master regulators, to express specific subsets of virulence factors required for survival and growth within different cells and tissues of the host. Salmonella is a model for studying intracellular pathogenesis without equal because of its established genetics and simple and inexpensive animal model - the mouse. Understanding how Salmonella survives and replicates within the host and how it expresses virulence genes at the appropriate time and place during infection will identify new therapeutic targets and provide a paradigm for understanding other pathogens.